Melphalan, also known as L-phenylalanine mustard, L-PAM or L-sarcolysin, is a phenyl alanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent that is active agent against selected human neoplastic diseases. Melphalan is structurally represented as
Melphalan is commercially supplied as freeze-dried or lyophilized powder with the brand names Alkeran® and Evomela®. Alkeran® for injection is supplied as a sterile, non-pyrogenic freeze-dried powder, where each vial of Alkeran® for injection contains melphalan hydrochloride equivalent to 50 mg of melphalan and 20 mg povidone. Alkeran® for injection is reconstituted with the sterile diluent provided that contains sodium citrate 0.2 g, propylene glycol 6.0 mL, ethanol (96%) 0.52 mL and water for injection to total of 10 mL. Alkeran® for injection is reconstituted with 10 mL of sterile diluent to provide a 5 mg/mL solution which is further diluted in 0.9% sodium chloride injection to have a concentration of not greater than 0.45 mL and administered intravenously over a period of minimum 15 minutes for the palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate.
Evomela® for injection is supplied as a sterile white-to-off white lyophilized powder in a single-dose vial for intravenous use. Each vial of Evomela® contains 50 mg melphalan free base equivalent to 56 mg melphalan hydrochloride and 2700 mg Betadex Sulfobutyl Ether Sodium NF. Evomela® vial is reconstituted with 8.6 mL of 0.9% sodium chloride injection to make a 50 mg/10 mL (5 mg/mL) nominal concentration of melphalan, which is further diluted with appropriate amount of 0.9% sodium chloride injection to a final concentration of 0.45 mg/mL and administered intravenously over a period of 15 to 20 minutes for the palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate and over a period of 30 minutes for high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma.
U.S. Pat. No. 4,997,651 discloses a pharmaceutical formulation of melphalan comprising as two separate components (a) freeze-dried melphalan hydrochloride, and (b) a solvent-diluent comprising a citrate, propylene glycol and ethanol.
US Patent Application Nos. 2010/031138, 2014/0213650 and 2014/0221488 disclose parenteral compositions comprising melphalan and a cyclodextrin derivative.
US Patent Application No. 2013/0131174 discloses a solid lyophilization composition of melphalan hydrochloride and a pH buffer solution, further comprising a sterile solution of sodium chloride at a concentration of between 0% and 10% providing a reconstitution composition of said melphalan hydrochloride lyophilized, said reconstitution composition being free of organic solvents.
RU 2060031 discloses parenteral lyophilized formulation comprising a melphalan, polyvinylpyrrolidone, ascorbic acid, glutamic acid, hydrochloric acid, and D-mannitol.
As the reconstitution of the lyophilized product is clinically inconvenient and the lyophilization process is time consuming the inventors of US Patent Application Nos. 2014/0005148 and US 2018/0193255 have developed the liquid formulation compositions of melphalan.
US Patent Application No. 2014/0005148 (US '148 Application) discloses the stable liquid formulation of melphalan comprising melphalan in an amount of about 0.1% w/w to about 10% w/w of the formulation, a non-aqueous liquid in an amount of about 45% w/w to about 98% w/w of the formulation, the non-aqueous liquid comprising a first solvent; and antioxidant in an amount of about 0.001% w/w to about 1% w/w of the formulation, an organic acid in an amount of about 0.02% w/w to about 1.5% w/w of the formulation; and a source of chloride ions in an amount of about 0.05% w/w to about 15% w/w of the formulation. The US '148 Application in Example-1 discloses the liquid formulations of melphalan, where one formulation contains melphalan 1% and Polyethylene glycol 99% without any stabilizers. The formulation of melphalan which does not contain stabilizers are detected with significant impurities after 72 hours when stored at 2° C.-8° C. The other formulations which comprise the antioxidant, organic acid (citric acid) and chloride ions source (sodium chloride) have shown the unexpected result that antioxidant, organic acid and chloride ion source combination can stabilize melphalan for a prolonged period of time at 25° C. and 40° C.
US Patent Application No. 2018/0193255 (US '255 Application) discloses the stable liquid parenteral formulation consisting essentially of melphalan hydrochloride, one or more solvents selected from dimethyl acetamide, polyethylene glycol, ethanol, propylene glycol and glycerine and anti-oxidants selected from monothioglycerol and L-cysteine wherein the formulation is free of organic acid and added chloride ions. US '355 Application further discloses that surprisingly there is no significant increase in total impurities at 25° C./60% RH with the liquid formulation of melphalan comprising of one or more solvents selected from DMA, ethanol, PEG and propylene glycol in the presence of the anti-oxidant.
The inventors of the present application have developed a ready-to-dilute liquid formulation of melphalan which overcomes the disadvantages reported in the prior art. The present inventors have unexpectedly discovered that the ready-to-dilute liquid formulation consisting of melphalan and one or more solvents selected from group consisting dimethyl acetamide, polyethylene glycol, ethanol, propylene glycol, dimethyl sulfoxide, N-methylpyrrolidone and glycerol, wherein formulation is free of antioxidants, organic acid and added chloride ions is stable for at least 6 months when stored at 2° C.-8° C.